Isolation and physical characterization of membrane proteins remains a central challenge in biomolecular sciences. Three-dimensional structure determination for membrane proteins, for example, has been successful only within the past two decades, and the set of known membrane protein structures is far smaller than the set of known soluble protein structures. Synthetic amphiphiles, such as detergents, are important tools in this field. They are used to extract embedded proteins from the membranes in which they naturally occur and maintain native protein conformation in the solubilized state. Physical characterization is often carried out with protein-amphiphile complexes, and such complexes are usually the basis for crystallization efforts. Growth of high-quality crystals is typically a rate-limiting step in structure determination. In light of the central role played by synthetic amphiphiles in membrane protein science, surprisingly little effort has been devoted to exploration of non-traditional architectures for these small molecules.
Many available detergents feature a lipophilic segment that is very flexible. This property may facilitate membrane protein solubilization, by allowing detergent molecules to accommodate themselves to lipophilic protein surfaces. However, flexibility could discourage crystallization of a protein-detergent complex, which requires molecular order. A balance between flexibility and rigidity is presumably necessary for maximum utility.
“Tripod amphiphiles,” such as Tripod A, were intended to meet the need for new types of synthetic agents that could be used in place of standard detergents for membrane protein manipulation.

The branchpoint in Tripod A imposes partial conformational restriction on the lipophilic segment because torsional motions are limited for bonds near the tetrasubstituted carbon. Both bacteriorhodopsin (bR) and bovine rhodopsin are effectively solubilized by Tripod A, and the resulting protein solutions are stable for several weeks. Two proteins, bR and a potassium channel from S. lividans, have been crystallized after solubilization by Tripod A, although no structures have been solved. U.S. Pat. No. 6,172,262 (McQuade et al.), incorporated herein by reference, discloses Tripod A and various related amphiphilic detergents of this general design.
In view of the limited detergents available for solubilization and stabilization of membrane proteins, there exists a need in the field for alternative detergents with expanded, alternate, and/or unique solubilization and protein stabilization properties.